Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDSATGA)

• DOT Name: Fibroblast growth factor 10 (FGF10)
• Synonyms: FGF-10; Keratinocyte growth factor 2
• Gene Name: FGF10
• Related Disease:
  LADD syndrome 1
  Lacrimoauriculodentodigital syndrome 3
  Aplasia of lacrimal and salivary glands
  LADD syndrome
• UniProt ID: FGF10_HUMAN
• PDB ID: 1NUN
• Pfam ID: PF00167
• Sequence:
  MWKWILTHCASAFPHLPGCCCCCFLLLFLVSSVPVTCQALGQDMVSPEATNSSSSSFSSP
  SSAGRHVRSYNHLQGDVRWRKLFSFTKYFLKIEKNGKVSGTKKENCPYSILEITSVEIGV
  VAVKAINSNYYLAMNKKGKLYGSKEFNNDCKLKERIEENGYNTYASFNWQHNGRQMYVAL
  NGKGAPRRGQKTRRKNTSAHFLPMVVHS
• Function: Plays an important role in the regulation of embryonic development, cell proliferation and cell differentiation. Required for normal branching morphogenesis. May play a role in wound healing.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  Calcium sig.ling pathway (hsa04020)
  PI3K-Akt sig.ling pathway (hsa04151)
  Regulation of actin cytoskeleton (hsa04810)
  Pathways in cancer (hsa05200)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Melanoma (hsa05218)
  Breast cancer (hsa05224)
  Gastric cancer (hsa05226)
• Reactome Pathway:
  (FGFR2)
  PIP3 activates AKT signaling (R-HSA-1257604)
  FGFR1b ligand binding and activation (R-HSA-190370)
  FGFR2b ligand binding and activation (R-HSA-190377)
  Activated point mutants of FGFR2 (R-HSA-2033519)
  Regulation of gene expression in early pancreatic precursor cells (R-HSA-210747)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  Phospholipase C-mediated cascade (R-HSA-5654219)
  Phospholipase C-mediated cascade (R-HSA-5654221)
  Downstream signaling of activated FGFR1 (R-HSA-5654687)
  SHC-mediated cascade (R-HSA-5654688)
  PI-3K cascade (R-HSA-5654689)
  FRS-mediated FGFR1 signaling (R-HSA-5654693)
  PI-3K cascade (R-HSA-5654695)
  SHC-mediated cascade (R-HSA-5654699)
  FRS-mediated FGFR2 signaling (R-HSA-5654700)
  Negative regulation of FGFR1 signaling (R-HSA-5654726)
  Negative regulation of FGFR2 signaling (R-HSA-5654727)
  Signaling by FGFR2 in disease (R-HSA-5655253)
  FGFRL1 modulation of FGFR1 signaling (R-HSA-5658623)
  RAF/MAP kinase cascade (R-HSA-5673001)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  PI3K Cascade (R-HSA-109704)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
LADD syndrome 1	DISHGCOR	Definitive	Autosomal dominant	[1]
Lacrimoauriculodentodigital syndrome 3	DISX1KHE	Strong	Autosomal dominant	[2]
Aplasia of lacrimal and salivary glands	DISHF35B	Supportive	Autosomal dominant	[3]
LADD syndrome	DISH8TQ5	Supportive	Autosomal dominant	[4]

4 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Fibroblast growth factor 10 (FGF10).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Fibroblast growth factor 10 (FGF10).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Fibroblast growth factor 10 (FGF10).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Fibroblast growth factor 10 (FGF10).	[11]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Fibroblast growth factor 10 (FGF10).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Fibroblast growth factor 10 (FGF10).	[10]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Chondroitin sulfate	DM0N19Y	Phase 4	Chondroitin sulfate affects the binding of Fibroblast growth factor 10 (FGF10).	[9]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the secretion of Fibroblast growth factor 10 (FGF10).	[12]

References

• [1] Mutations in different components of FGF signaling in LADD syndrome. Nat Genet. 2006 Apr;38(4):414-7. doi: 10.1038/ng1757. Epub 2006 Feb 26.
• [2] Mutations in the gene encoding fibroblast growth factor 10 are associated with aplasia of lacrimal and salivary glands. Nat Genet. 2005 Feb;37(2):125-7. doi: 10.1038/ng1507. Epub 2005 Jan 16.
• [3] FGF10 missense mutations in aplasia of lacrimal and salivary glands (ALSG). Eur J Hum Genet. 2007 Mar;15(3):379-82. doi: 10.1038/sj.ejhg.5201762. Epub 2007 Jan 10.
• [4] LADD syndrome is caused by FGF10 mutations. Clin Genet. 2006 Apr;69(4):349-54. doi: 10.1111/j.1399-0004.2006.00597.x.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [7] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Specific molecular interactions of oversulfated chondroitin sulfate E with various heparin-binding growth factors. Implications as a physiological binding partner in the brain and other tissues. J Biol Chem. 2002 Nov 15;277(46):43707-16. doi: 10.1074/jbc.M207105200. Epub 2002 Sep 6.
• [10] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [11] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [12] Effects of Agricultural Organic Dusts on Human Lung-Resident Mesenchymal Stem (Stromal) Cell Function. Toxicol Sci. 2018 Apr 1;162(2):635-644. doi: 10.1093/toxsci/kfx286.